The autosomal recessive mutation wobbler of the mouse (phenotype WR; genotype wr/wr) causes muscular atrophy due to motoneuron degeneration with 100% penetrance on the standard Mus musculus laboratorius C57BL/6J background. In inter- and backcrosses with M. m. castaneus strain CAST/EI we have observed a variability in the severity of neurological symptoms. Approximately 15% of the WR (wr/wr) CAST/B6 hybrids were modified wobbler (WR*) mice defined by an aggravated neuromuscular phenotype with hindlimbs severely affected in addition to forelimbs. Histologically the overt WR* phenotype was paralleled by a caudally extended neurodegeneration in the ventral horn of the spinal cord with severe astrogliosis, and levels of acetylcholine receptor alpha-subunit mRNA in leg muscle much higher than in standard WR mice. Segregation analysis, using 68 polymorphic autosomal markers in a whole genome scan, revealed a major modifier gene locus, termed wrmod1, on chromosome 14. Individual recombination events in chromosome 14 consomic mice narrowed the wrmod1 candidate region to a 29 cM interval between D14MIT154 and D14MIT105, a region homologous to human chromosome 13q. Our analysis provides access to genes that modify neurodegeneration, the human counterparts of which may be responsible for the variable expression of hereditary spinal muscular atrophies.
BackgroundTo support the positional cloning of the mouse mutation wobbler (wr) the corresponding regions on human Chr2p13-14 and mouse Chr11 were analyzed in detail and compared with respect to gene content, order, and orientation.ResultsThe gene content of the investigated regions was highly conserved between the two species: 20 orthologous genes were identified on our BAC/YAC contig comprising 4.5 Mb between REL/Rel and RAB1A/Rab1a. Exceptions were pseudogenes ELP and PX19 whose mouse counterparts were not located within the analyzed region. Two independently isolated genomic clones indicate an inversion between man and mouse with the inverted segment being identical to the wobbler critical interval. We investigated the wobbler critical region by extensive STS/EST mapping and genomic sequencing. Additionally, the full-length cDNA sequences of four newly mapped genes as well as the previously mapped gene Otx1 were established and subjected to mutation analysis. Our data indicate that all genes in the wr critical region have been identified.ConclusionUnexpectedly, neither mutation analysis of cDNAs nor levels of mRNAs indicated which of the candidate genes might be affected by the wr mutation. The possibility arises that there might be hitherto unknown effects of mutations, in addition to structural changes of the mRNA or regulatory abnormalities.
Background: To support the positional cloning of the mouse mutation wobbler (wr) the corresponding regions on human Chr2p13-14 and mouse Chr11 were analyzed in detail and compared with respect to gene content, order, and orientation. Results: The gene content of the investigated regions was highly conserved between the two species: 20 orthologous genes were identified on our BAC/YAC contig comprising 4.5 Mb between REL/Rel and RAB1A/Rab1a. Exceptions were pseudogenes ELP and PX19 whose mouse counterparts were not located within the analyzed region. Two independently isolated genomic clones indicate an inversion between man and mouse with the inverted segment being identical to the wobbler critical interval. We investigated the wobbler critical region by extensive STS/EST mapping and genomic sequencing. Additionally, the full-length cDNA sequences of four newly mapped genes as well as the previously mapped gene Otx1 were established and subjected to mutation analysis. Our data indicate that all genes in the wr critical region have been identified. Conclusion: Unexpectedly, neither mutation analysis of cDNAs nor levels of mRNAs indicated which of the candidate genes might be affected by the wr mutation. The possibility arises that there might be hitherto unknown effects of mutations, in addition to structural changes of the mRNA or regulatory abnormalities.
ZusammenfassungDer rechtlich geklärte Verzicht auf Bluttransfusionen, wie er bei Zeugen Jehovas (ZJ) zu praktizieren ist, führte zur Entwicklung leistungsfähiger, individualisierter Anästhesieverfahren und Operationstechniken. Vorreiter war die Arbeitsgruppe um Cooley am Texas Heart Institute Anfang der 60er Jahre. Über die chirurgische Behandlung von ZJ in der Urologie gibt es nur kasuistische Beiträge. Die Resultate der Vorgehensweise bei 70 ZJ sind in einer retrospektiven Studie überprüft worden. Patienten und Methode: Bei 61 Erwachsenen (Durchschnittsalter 61 Jahre) und 9 Kindern (Altersmedian 6,23 Jahre) wurden 80 Operationen vorgenommen. Die präoperativen hämatologischen Befunde waren bei 81,3 % der Erwachsenen und allen Kindern im Normbereich. 2/61 Erwachsene hatten bei normaler partieller Thromboplastizität Quick-Werte von 30 % und 61 %. Von den 80 Operationen wurden 30 als blutungsbedroht eingestuft, die restlichen, einschlieûlich der 9 Eingriffe bei Kindern, als blutungsarm. Der häufigste Eingriff (n = 17) der ersteren war die radikale retropubische Prostatektomie, der letzteren die transurethrale Prostataresektion (n = 14). Nur 7 % der Patienten mit blutungsbedrohten Eingriffen hatten keinen Risikofaktor, aber 91,7 % wurden in der ASA-Klasse 1 und 2 eingestuft. Von den Eingriffen mit hohem Blutungsrisiko wurden 8,3 % als ASA-Klasse 3, aber keiner höher klassifiziert. Die ethisch-rechtliche Situation war bei jedem ZJ geregelt (Dokumente zur ärztlichen Versorgung). Operationstaktisch wurde die Kompartmenttechnik gewählt. Ergebnisse: Bei den blutungsarmen Eingriffen der Kinder war die perioperative Phase nicht gestört. Bei 13 % der Erwachsenen kam es anästhesiebedingt zu einem nicht bedrohlichen Blutdruckabfall auf maximal 60/40 mm Hg ohne krankheitsrelevanten Hb-Abfall, bei allen wurde eine transurethrale Prostataresektion durchgeführt. Die Liegezeit betrug durchschnittlich 10,5 Tage. Bei 30 blutungsbedrohten Eingriffen betrug die durchschnittliche Operationsdauer 2,5 Stunden und bei hohem Blutungsrisiko 3,4 Stunden. 29,2 % hatten eine Peridural-und Intubationsnarkose, 10 % eine kontrollierte Hypotension. Operationsbedingt fiel der Hb-Wert bei 92 % der Patienten mit hohem Blu-tungsrisiko unter den Normalwert. 2 Frauen hatten einen Hb-Nadir von 5,0 und 4,9 g/100 ml ohne hierdurch bedingte Komplikationen. Ein Patient verstarb bei einem postoperativen Hb von 10,5 g/100 ml an einer autoptisch gesicherten Lungenembolie. Die Liegezeit für Patienten nach blutungsbedrohten Eingriffen betrug 19,5 Tage, für Patienten mit hohem Blutungsrisiko 23,9 Tage. Schlussfolgerung: Im Einklang mit den im wissenschaftlichen Schrifttum widergegebenen Erfahrungen lieû sich in dieser Studie zeigen, dass blutersatzfreies Operieren auch bei groûen Eingriffen in der Urologie möglich ist. AbstractThe refusal of blood transfusion by Jehovas Witnesses (JW) stimulated the development of problem-oriented anesthesiological and surgical techniques. A pioneer of bloodless surgery was Cooley at the Texas Heart Institute in the Sixties. Howev...
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